Premature closure of the neurocranial sutures, craniosynostosis, is a relatively common bir6th defect that results in increased intracranial pressure and abnormal head shape. The condition necessitates reconstructive surgery during the first months of life and therefore represents a significant public health problem. Craniosynostosis is one of a number of clinical features in over 100 syndromes. Some of these syndromes, specifically Crouzon, Apert, Jackson-Weiss, Pfeiffer, and Saethre-Chotzen, exhibit similarities in craniofacial phenotypes. Craniosynostosis can also occur as an apparently isolated phenomenon. Recent reviews note that over 64 different mutations of seven genes are responsible for craniosynostosis syndromes and that a single, but highly variable mutation is responsible for a large proportion of non-syndromic coronal synostosis. As of this writing, no specific mutations have been found to be associated with isolated sagittal or isolated metopic synostosis. The long-term goal of the proposed project is to determine the role of genes associated with craniosynostosis in producing craniofacial phenotypes. This will be done by obtaining objective, quantitative measures of the craniofacial phenotypes of the craniosynostosis syndromes named above and for isolated cases for metopic, sagittal, and coronal synostosis, and by identifying the genetic mutations present in this population. Individual phenotypic characterizations will be based on three-dimensional craniofacial image data. The quantitative, three-dimensional, craniofacial characterizations will be analyzed to determine groups of individuals defined solely on the basis of cutaneous, skeletal, and/or CNS craniofacial morphology. Any correspondence between the morphological groups and the genetic mutations present in these individuals will provide an unbiased genotype-phenotype correlation. Explanations of the craniofacial phenotypic variability within our morphological groups will be sought using additional clinical data. These data include standard demographic data, epidemiological factors implicated in the occurrence of some craniosynostosis conditions, and clinical evaluations of neuropsychological function.